Coordinated Proteins Aid the Immune System in Detecting and Destroying Threats

The immune system tackles bacteria, parasites, and viruses. Cells known as macrophages are at the forefront of the human immune response, recognizing intruders and controlling how the entire immune system responds. Researchers at the Salk Institute have uncovered a molecular mechanism that enables macrophages to produce a coordinated response customized to a particular immune challenge.

Three forms of the SWI/SNF protein complex are required to activate macrophages: cBAF, ncBAF, and PBAF. Scientists already recognized that some variations had slightly different structures, but new findings show that these discrepancies have actual functional repercussions. Salk researchers observed that each variant has a unique role in initiating macrophage responses to intruders and, as a result, how the immune system controls inflammation.

By identifying these SWI/SNF variants, the researchers discovered new immune system processes that could be targeted with treatments to control inflammation connected with conditions such as sepsis, cytokine storm, COVID-19, and others.

The results were published in Immunity on June 5^th, 2024.

Macrophages are our first line of defense and the recruiters for adaptive immune cells, so understanding how they work is key to understanding our immune response. If we can figure out how macrophages tailor their responses to a given immune signal, we’ll have a better idea of how we can therapeutically target them to create desirable immune system behaviors.”

Diana Hargreaves, Study Senior Author and Associate Professor, Salk Institute

Macrophages are the first to detect an intruder in the body, thus it is their role to correctly identify the intruder and instruct the immune system's reaction. Macrophages require highly specialized internal communication to mount the appropriate response.

Each macrophage includes a set of identity-forming instructions encoded in DNA strands that are wrapped around histone protein complexes before being bundled into a 3D structure known as chromatin. Changes to histones and chromatin have an influence on a cell’s identity because they can reveal or conceal stretches of DNA that control the cell’s activity.

The SWI/SNF protein complex was already known to cause such modifications, but it was unclear whether each of the three variants did so in a unique manner or resulted in diverse macrophage behavior. To understand more about the SWI/SNF variants, the researchers studied how macrophages in mice responded to bacterial infection, focusing on changes in cBAF, ncBAF, and PBAF activity.

We found the SWI/SNF variants each serve a unique, important purpose in reorganizing chromatin across the genome and enabling macrophage inflammatory responses. This is a major leap in our understanding of how immune systems respond with such a high level of specificity.”

Jingwen Liao, Study First Author and Graduate Student, Salk Institute

When presented with a bacterial challenge, each of the three SWI/SNF variants controlled different regions of the macrophages’ DNA, resulting in varied cellular responses. cBAF redesigned chromatin to increase inflammation, but ncBAF altered histones to activate an antiviral response. PBAF also modified histones, although the results were less obvious than with cBAF or ncBAF.

The three operated separately and cooperatively to orchestrate a complex immune response that relies on the rest of the immune system to effectively and efficiently clear the body of threats.

Hargreaves further added, “Chronic inflammation is a major cause of mortality across many diseases. When patients succumb to COVID, for example, that’s often a product of inflammation. This makes our findings really exciting, because we’ve found a new way to potentially toggle the immune system’s inflammatory pathways to improve outcomes in patients with chronic inflammation.”

In further studies, the researchers will investigate the impact of PBAF-induced histone modification. Given that cBAF and ncBAF inhibitors are currently in clinical trials for cancer treatment, Hargreaves believes their results will be translated into future chronic inflammation drugs.

Mannix Burns and Josephine Ho from Salk as well as Emily Dykhuizen from Purdue University are additional writers.